What is Tacrine?

Introduction

Tacrine is a centrally acting acetylcholinesterase inhibitor and indirect cholinergic agonist (parasympathomimetic).

It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer’s disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the University of Sydney in 1949. It also acts as a histamine N-methyltransferase inhibitor.

Clinical Use

Tacrine was the prototypical cholinesterase inhibitor for the treatment of Alzheimer’s disease. William K. Summers received a patent for this use in 1989. Studies found that it may have a small beneficial effect on cognition and other clinical measures, though study data was limited and the clinical relevance of these findings was unclear.

Tacrine has been discontinued in the US in 2013, due to concerns over safety.

Tacrine was also described as an analeptic agent used to promote mental alertness.

Adverse Effects

  • Very common (>10% incidence) adverse effects include:
    • Increased LFTs.
    • Nausea.
    • Vomiting.
    • Diarrhoea.
    • Headache.
    • Dizziness.
  • Common (1-10% incidence) adverse effects include:
    • Indigestion.
    • Belching.
    • Abdominal pain.
    • Myalgia – muscle pain.
    • Confusion.
    • Ataxia – decreased control over bodily movements.
    • Insomnia.
    • Rhinitis.
    • Rash.
    • Fatigue.
    • Weight loss.
    • Constipation.
    • Somnolence.
    • Tremor.
    • Anxiety.
    • Urinary incontinence.
    • Hallucinations.
    • Agitation.
    • Conjunctivitis (a link to tacrine treatment has not been conclusively proven).
    • Diaphoresis – sweating.
  • Uncommon/rare (<1% incidence) adverse effects include:
    • Hepatotoxicity (that is toxic effects on the liver).
    • Ototoxicity (hearing/ear damage; a link to tacrine treatment has not been conclusively proven).
    • Seizures.
    • Agranulocytosis (a link between treatment and this adverse effect has not been proven) – a potentially fatal drop in white blood cells, the body’s immune/defensive cells.
    • Taste changes.
  • Unknown incidence adverse effects include:
    • Urinary tract infection.
    • Delirium.
    • Other optic effects such as glaucoma, cataracts, etc. (also not conclusively linked to tacrine treatment).
    • Depression.
    • Suicidal ideation and behaviour.
    • Hypotension.
    • Bradycardia.

Overdose

As stated above, overdosage of tacrine may give rise to severe side effects such as nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Atropine is a popular treatment for overdose.

Pharmacokinetics

Major form of metabolism is in the liver via hydroxylation of benzylic carbon by CYP1A2. This forms the major metabolite 1-hydroxy-tacrine (velnacrine) which is still active.

What is a Serotonergic Drug?

Introduction

Serotonergic means “pertaining to or affecting serotonin”.

Background

Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron produces serotonin. A substance is serotonergic if it produces its effects via interactions with the serotonin system, such as by stimulating or blocking neurotransmission.

A serotonergic or serotoninergic agent is any chemical that modifies the effects of serotonin in the body. Some different types of serotonergics drugs include the following:

  • Serotonin receptor agonists and antagonists;
  • Serotonin reuptake inhibitors; and
  • Serotonin releasing agents.

What is Triazolam?

Introduction

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives.

It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam’s amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced, as well. Due to its short half-life, triazolam is not effective for patients who experience frequent awakenings or early wakening.

Triazolam was initially patented in 1970 and went on sale in the United States in 1982. In 2017, it was the 280th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical Uses

Triazolam is usually used for short-term treatment of acute insomnia and circadian rhythm sleep disorders, including jet lag. It is an ideal benzodiazepine for this use because of its fast onset of action and short half-life. It puts a person to sleep for about 1.5 hours, allowing its user to avoid morning drowsiness. Triazolam is also sometimes used as an adjuvant in medical procedures requiring anaesthesia or to reduce anxiety during brief events, such as MRI scans and nonsurgical dental procedures. Triazolam is ineffective in maintaining sleep, however, due to its short half-life, with quazepam showing superiority.

Triazolam is frequently prescribed as a sleep aid for passengers travelling on short- to medium-duration flights. If this use is contemplated, the user avoiding the consumption of alcoholic beverages is especially important, as is trying a ground-based “rehearsal” of the medication to ensure that the side effects and potency of this medication are understood by the user prior to using it in a relatively more public environment (as disinhibition can be a common side effect, with potentially severe consequences). Triazolam causes anterograde amnesia, which is why so many dentists administer it to patients undergoing even minor dental procedures. This practice is known as sedation dentistry.

Side Effects

Adverse drug reactions associated with the use of triazolam include:

  • Relatively common (>1% of patients): somnolence, dizziness, feeling of lightness, coordination problems.
  • Less common (0.9% to 0.5% of patients): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances.
  • Rare (<0.5% of patients): constipation, taste alteration, diarrhoea, dry mouth, dermatitis/allergy, dreams/nightmares, insomnia, paraesthesia, tinnitus, dysesthesia, weakness, congestion.

Triazolam, although a short-acting benzodiazepine, may cause residual impairment into the next day, especially the next morning. A meta-analysis demonstrated that residual “hangover” effects after night-time administration of triazolam such as sleepiness, psychomotor impairment, and diminished cognitive functions may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures. Confusion and amnesia have been reported.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance, Dependence, and Withdrawal

Refer to Benzodiazepine Withdrawal Syndrome.

A review of the literature found that long-term use of benzodiazepines, including triazolam, is associated with drug tolerance, drug dependence, rebound insomnia, and CNS-related adverse effects. Benzodiazepine hypnotics should be used at their lowest possible dose and for a short period of time. Nonpharmacological treatment options were found to yield sustained improvements in sleep quality. A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam, even following short-term, single-dose therapy.

Other withdrawal symptoms can range from mild unpleasant feelings to a major withdrawal syndrome, including stomach cramps, vomiting, muscle cramps, sweating, tremor, and in rare cases, convulsions.

Contraindications

Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, in alcoholics, or in other drug-dependent individuals and individuals with comorbid psychiatric disorders. Triazolam belongs to the Pregnancy Category X of the FDA. It is known to have the potential to cause birth defects.

Elderly

Triazolam, similar to other benzodiazepines and nonbenzodiazepines, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments. Daytime withdrawal effects can occur.

An extensive review of the medical literature regarding the management of insomnia and the elderly found considerable evidence of the effectiveness and durability of nondrug treatments for insomnia in adults of all ages and that these interventions are underused. Compared with the benzodiazepines including triazolam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment, anterograde amnesia, daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.

In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Interactions

Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects. Anxiety, tremor, and depression have been documented in a case report following administration of nitrazepam and triazolam. Following administration of erythromycin, repetitive hallucinations and abnormal bodily sensations developed. The patient had, however, acute pneumonia, and kidney failure. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in those with other physical complications. Caffeine reduces the effectiveness of triazolam. Other important interactions include cimetidine, diltiazem, fluconazole, grapefruit juice, isoniazid, itraconazole, nefazodone, rifampicin, ritonavir, and troleandomycin. Triazolam should not be administered to patients on Atripla.

Overdose

Refer to Benzodiazepine Overdose.

Symptoms of an overdose include:

  • Coma.
  • Hypoventilation (respiratory depression).
  • Somnolence (drowsiness).
  • Slurred speech.
  • Seizures.

Death can occur from triazolam overdose, but is more likely to occur in combination with other depressant drugs such as opioids, alcohol, or tricyclic antidepressants.

Pharmacology

The pharmacological effects of triazolam are similar to those of most other benzodiazepines. It does not generate active metabolites. Triazolam is a short-acting benzodiazepine, is lipophilic, and is metabolised hepatically via oxidative pathways. The main pharmacological effects of triazolam are the enhancement of the neurotransmitter GABA at the GABAA receptor. The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug. It has anticonvulsant effects on brain function.

Society and Culture

Recreational Use

Refer to Benzodiazepine Drug Misuse.

Triazolam issued nonmedically: recreational use wherein the drug is taken to achieve a high or continued long-term dosing against medical advice.

Legal Status

Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances and the US Controlled Substances Act.

Brandnames

The drug is marketed in English-speaking countries under the brand names Apo-Triazo, Halcion, Hypam, and Trilam. Other (designer) names include 2′-chloroxanax, chloroxanax, triclazolam, and chlorotriazolam.

What is Zimelidine?

Introduction

Zimelidine (INN, BAN) (brand names Zimeldine, Normud, Zelmid) was one of the first selective serotonin reuptake inhibitor (SSRI) antidepressants to be marketed.

It is a pyridylallylamine, and is structurally different from other antidepressants.

Zimelidine was developed in the late 1970s and early 1980s by Arvid Carlsson, who was then working for the Swedish company Astra AB. It was discovered following a search for drugs with structures similar to brompheniramine (it is a derivative of brompheniramine), an antihistamine with antidepressant activity. Zimelidine was first sold in 1982.

While zimelidine had a very favourable safety profile, within a year and a half of its introduction, rare case reports of Guillain–Barré syndrome emerged that appeared to be caused by the drug, prompting its manufacturer to withdraw it from the market. After its withdrawal, it was succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) in that order, and the other SSRIs.

Mechanism of Action

The mode of action is a strong reuptake inhibition of serotonin from the synaptic cleft. Postsynaptic receptors are not acted upon.

Other Uses

Zimelidine was reported by Montplaisir and Godbout to be very effective for cataplexy in 1986, back when this was usually controlled by tricyclic antidepressants, which often had anticholinergic effects. Zimelidine was able to improve cataplexy without causing daytime sleepiness.

Side Effects

Most often reported were:

  • Dry mouth, dryness of pharyngeal and nasal membranes.
  • Increased sweating (hyperhidrosis).
  • Vertigo.
  • Nausea.

Interactions

MAO inhibitors – severe or life-threatening reactions possible.

What is Escitalopram?

Introduction

Escitalopram, sold under the brand names Cipralex and Lexapro, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder (MDD) or generalised anxiety disorder (GAD). It is taken by mouth.

Common side effects include trouble sleeping, nausea, sexual problems, and feeling tired. More serious side effects may include suicide in people under the age of 25. It is unclear if use during pregnancy or breastfeeding is safe. Escitalopram is the (S)-stereoisomer (left-handed version) of citalopram (which exists as a racemate), hence the name escitalopram. In other words, escitalopram is a chiral switch of citalopram.

Escitalopram was approved for medical use in the United States in 2002. Escitalopram is sometimes replaced by twice the dose of citalopram. In 2018, it was the 22nd most commonly prescribed medication in the United States with more than 25 million prescriptions.

Brief History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.

The FDA issued the approval of escitalopram for major depression in August 2002 and for GAD in December 2003. On 23 May 2006, the FDA approved a generic version of escitalopram by Teva. On 14 July of that year, however, the US District Court of Delaware decided in favour of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.

In 2006, Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram. This pushed the patent expiration date from 07 December 2009, to 14 September 2011. Together with the 6-month paediatric exclusivity, the final expiration date was 14 March 2012.

Medical Uses

Escitalopram has FDA approval for the treatment of major depressive disorder in adolescents and adults, and generalized anxiety disorder in adults. In European countries and the United Kingdom, it is approved for depression (MDD) and anxiety disorders, these include: GAD, social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder with or without agoraphobia. In Australia it is approved for major depressive disorder.

Depression

Escitalopram was approved by regulatory authorities for the treatment of major depressive disorder on the basis of four placebo-controlled, double-blind trials, three of which demonstrated a statistical superiority over placebo.

Controversy existed regarding the effectiveness of escitalopram compared with its predecessor, citalopram. The importance of this issue followed from the greater cost of escitalopram relative to the generic mixture of isomers of citalopram, prior to the expiration of the escitalopram patent in 2012, which led to charges of evergreening. Accordingly, this issue has been examined in at least 10 different systematic reviews and meta analyses. As of 2012, reviews had concluded (with caveats in some cases) that escitalopram is modestly superior to citalopram in efficacy and tolerability.

A 2011 review concluded that second-generation antidepressants appear equally effective, although they may differ in onset and side effects. Treatment guidelines issued by the National Institute of Health and Clinical Excellence and by the American Psychiatric Association generally reflect this viewpoint.

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective.

Anxiety Disorder

Escitalopram appears to be effective in treating general anxiety disorder, with relapse on escitalopram at 20% rather than placebo at 50%.

Escitalopram appears effective in treating social anxiety disorder.

Other

Escitalopram is effective in reducing the symptoms of premenstrual syndrome, whether taken continuously or in the luteal phase only. There are no good data available for escitalopram as treatment for seasonal affective disorder as of 2021.

Side Effects

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, delayed ejaculation, and anorgasmia.

There is also evidence that SSRIs may cause an increase in suicidal ideation. An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications. The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients.

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in those with congenital long QT syndrome or known pre-existing QT interval prolongation, or in combination with other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. In December 2011, the UK implemented new restrictions on the maximum daily doses at 20 mg for adults and 10 mg for those older than 65 years or with liver impairment. There are concerns of higher rates of QT prolongation and torsades de pointes compared with other SSRIs. The US Food and Drug Administration (FDA) and Health Canada did not similarly order restrictions on escitalopram dosage, only on its predecessor citalopram.

Very Common Effects

Very common effects (>10% incidence) include:

  • Headache (24%).
  • Nausea (18%).
  • Ejaculation disorder (9-14%).
  • Somnolence (4-13%).
  • Insomnia (7-12%).

Common Effects

Common effects (1-10% incidence) include:

  • Insomnia.
  • Somnolence (sleepiness).
  • Dizziness.
  • Paraesthesia.
  • Tremor.
  • Decreased or increased appetite.
  • Anxiety.
  • Restlessness.
  • Abnormal dreams.
  • Libido decreased.
  • Anorgasmia.
  • Sinusitis (nasal congestion).
  • Yawning.
  • Diarrhoea.
  • Constipation.
  • Vomiting.
  • Dry mouth.
  • Excessive sweating.
  • Arthralgia (joint pain).
  • Myalgia (muscular aches and pains).
  • Fatigue.
  • Pyrexia (fever).
  • Impotence (erectile dysfunction).

Psychomotor Effects

The most common effect is fatigue or somnolence, particularly in older adults, although patients with pre-existing daytime sleepiness and fatigue may experience paradoxical improvement of these symptoms. Escitalopram has not been shown to affect serial reaction time, logical reasoning, serial subtraction, multitask, or MacWorth clock task performance.

Discontinuation Symptoms

Refer to Antidepressant Discontinuation Syndrome.

Escitalopram discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as anhedonia (83%), “electric shock” sensations, colloquially called “brain shivers” or “brain zaps” by sufferers. Frequent symptoms in one study were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). Very slow tapering was recommended. There have been spontaneous reports of discontinuation of Lexapro and other SSRIs and SNRIs, especially when abrupt, leading to dysphoric mood, irritability, agitation, anxiety, headache, lethargy, emotional lability, insomnia, and hypomania. Other symptoms such as panic attacks, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), mania, worsening of depression, and suicidal ideation can emerge when the dose is adjusted down.

Sexual Dysfunction

Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as post-SSRI sexual dysfunction (PSSD). Common symptoms include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. Rates are unknown, and there is no established treatment.

Pregnancy

Antidepressant exposure (including escitalopram) is associated with shorter duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion. There is a tentative association of SSRI use during pregnancy with heart problems in the baby. The advantages of their use during pregnancy may thus outweigh the possible negative effects on the baby.

Overdose

Excessive doses of escitalopram usually cause relatively minor untoward effects, such as agitation and tachycardia. However, dyskinesia, hypertonia, and clonus may occur in some cases. Therapeutic blood levels of escitalopram are usually in the range of 20-80 μg/L but may reach 80-200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolisers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.

Pharmacology

Mechanism of Action

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently available, escitalopram has the highest selectivity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), making the side-effect profile relatively mild in comparison to less-selective SSRIs.

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood brain barrier penetrability. In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor, its antidepressant-like effects were enhanced.

Interactions

Escitalopram, similarly to other SSRIs, inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazole, risperidone, tramadol, codeine, etc. As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected. Escitalopram should be taken with caution when using St. John’s wort. Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole. The authors of this study suggested that this increase is unlikely to be of clinical concern. Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome has been reported.

Bupropion has been found to significantly increase citalopram plasma concentration and systemic exposure; as of April 2018 the interaction with escitalopram had not been studied, but some monographs warned of the potential interaction.

Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that also have the ability to prolong the QT interval. These drugs include antiarrhythmics, antipsychotics, tricyclic antidepressants, some antihistamines (astemizole, mizolastine) and some antiretrovirals (ritonavir, saquinavir, lopinavir). As an SSRI, escitalopram should generally not be given concurrently with MAOIs.

Chemistry

Escitalopram is the (S)-stereoisomer (left-handed version) of the racemate citalopram, which is responsible for its name: escitalopram. The (R)-stereoisomer (R-citalopram, the right-handed version) is not thought to have useful effects for treating depression.

Society and Culture

Allegations of Illegal Marketing

In 2004, separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers: a physician named Joseph Piacentile and a Forest salesman named Christopher Gobble. In February 2009, the suits were joined. Eleven states and the District of Columbia filed notices of intent to intervene as plaintiffs in the action.

The suits alleged that Forest illegally engaged in off-label promotion of Lexapro for use in children; hid the results of a study showing lack of effectiveness in children; paid kickbacks to physicians to induce them to prescribe Lexapro to children; and conducted so-called “seeding studies” that were, in reality, marketing efforts to promote the drug’s use by doctors. Forest denied the allegations but ultimately agreed to settle with the plaintiffs for over $313 million.

Brand Names

Escitalopram is sold under many brand names worldwide such as Cipralex, Lexapro, Mozarin, Aciprex, Depralin, Ecytara, Elicea, Nexpram, Pramatis, and Betesda.

What is Fluvoxamine?

Introduction

Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class which is used primarily for the treatment of depression disorder and obsessive-compulsive disorder (OCD). It is also used to treat anxiety disorders, such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.

Fluvoxamine’s side-effect profile is very similar to other SSRIs: constipation, gastrointestinal problems, headache, anxiety, irritation, sexual problems, dry mouth, sleep problems and a risk of suicide at the start of treatment by lifting the psychomotor inhibition, but these effects appear to be significantly weaker than with other SSRIs (except gastrointestinal side-effects). The tolerance profile also appears to be quite superior than other SSRIs, despite its age.

Anti-inflammatory effects of fluvoxamine are being researched to determine if it can be used to treat COVID-19. It is not approved by the US Federal Drug Administration (FDA) for treatment of any infection.

Brief History

Fluvoxamine was developed by Kali-Duphar, part of Solvay Pharmaceuticals, Belgium, now Abbott Laboratories, and introduced as Floxyfral in Switzerland in 1983. It was approved by the FDA in 1994, and introduced as Luvox in the US. In India, it is available, among several other brands, as Uvox by Abbott. It was one of the first SSRI antidepressants to be launched, and is prescribed in many countries to patients with major depression. It was the first SSRI, a non-TCA drug, approved by the FDA specifically for the treatment of OCD. At the end of 1995, more than ten million patients worldwide had been treated with fluvoxamine. Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997. In Japan, fluvoxamine was the first SSRI to be approved for the treatment of depression in 1999 and was later in 2005 the first drug to be approved for the treatment of social anxiety disorder. Fluvoxamine was the first SSRI approved for clinical use in the United Kingdom.

Medical Uses

In many countries (e.g. Australia, the UK, and Russia) it is commonly used for major depressive disorder. Fluvoxamine is also approved in the United States for OCD, and social anxiety disorder. In Japan it is also approved to treat OCD, social anxiety disorder (SAD) and major depressive disorder (MDD). Fluvoxamine is indicated for children and adolescents with OCD. The drug works long-term, and retains its therapeutic efficacy for at least one year. It has also been found to possess some analgesic properties in line with other SSRIs and tricyclic antidepressants.

There is tentative evidence that fluvoxamine is effective for social phobia in adults. Fluvoxamine is also effective for generalised anxiety disorder (GAD), SAD, panic disorder and separation anxiety disorder in children and adolescents. There is tentative evidence that fluvoxamine may help some people with negative symptoms of chronic schizophrenia.

Adverse Effects

Gastrointestinal side effects are more common in those receiving fluvoxamine than with other SSRIs. Otherwise, fluvoxamine’s side-effect profile is very similar to other SSRIs.

Common (1-10% Incidence) Adverse Effects

  • Nausea.
  • Vomiting.
  • Weight loss.
  • Yawning.
  • Loss of appetite.
  • Agitation.
  • Nervousness.
  • Anxiety.
  • Insomnia.
  • Somnolence (drowsiness).
  • Tremor.
  • Restlessness.
  • Headache.
  • Dizziness.
  • Palpitations.
  • Tachycardia (high heart rate).
  • Abdominal pain.
  • Dyspepsia (indigestion).
  • Diarrhoea.
  • Constipation.
  • Hyperhidrosis (excess sweating).
  • Asthenia (weakness).
  • Malaise.
  • Sexual dysfunction (including delayed ejaculation, erectile dysfunction, decreased libido, etc.).
  • Xerostomia (dry mouth).

Uncommon (0.1-1% Incidence) Adverse Effects

  • Arthralgia.
  • Hallucination.
  • Confusional state.
  • Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, etc.).
  • Orthostatic hypotension.
  • Cutaneous hypersensitivity reactions (e.g. oedema [buildup of fluid in the tissues], rash, pruritus).

Rare (0.01-0.1% Incidence) Adverse Effects

  • Mania.
  • Seizures.
  • Abnormal hepatic (liver) function.
  • Photosensitivity (being abnormally sensitive to light).
  • Galactorrhoea (expulsion of breast milk unrelated to pregnancy or breastfeeding).

Unknown Frequency Adverse Effects

  • Hyperprolactinaemia (elevated plasma prolactin levels leading to galactorrhoea, amenorrhoea [cessation of menstrual cycles], etc.).
  • Bone fractures.
  • Glaucoma.
  • Mydriasis.
  • Urinary incontinence.
  • Urinary retention.
  • Bed-wetting.
  • Serotonin syndrome: A potentially fatal condition characterised by abrupt onset muscle rigidity, hyperthermia (elevated body temperature), rhabdomyolysis, mental status changes (e.g. coma, hallucinations, agitation), etc.
  • Neuroleptic malignant syndrome – practically identical presentation to serotonin syndrome except with a more prolonged onset.
  • Akathisia – a sense of inner restlessness that presents itself with the inability to stay still.
  • Paraesthesia.
  • Dysgeusia.
  • Haemorrhage.
  • Withdrawal symptoms.
  • Weight changes.
  • Suicidal ideation and behaviour.
  • Violence towards others.
  • Hyponatraemia.
  • Syndrome of inappropriate antidiuretic hormone secretion.
  • Ecchymoses.

Interactions

Fluvoxamine inhibits the following cytochrome P450 enzymes:

  • CYP1A2 (strongly) which metabolises agomelatine, amitriptyline, caffeine, clomipramine, clozapine, duloxetine, haloperidol, imipramine, phenacetin, tacrine, tamoxifen, theophylline, olanzapine, etc.
  • CYP3A4 (moderately) which metabolises alprazolam, aripiprazole, clozapine, haloperidol, quetiapine, pimozide, ziprasidone, etc.
  • CYP2D6 (weakly) which metabolises aripiprazole, chlorpromazine, clozapine, codeine, fluoxetine, haloperidol, olanzapine, oxycodone, paroxetine, perphenazine, pethidine, risperidone, sertraline, thioridazine, zuclopenthixol, etc.[43]
  • CYP2C9 (moderately) which metabolises nonsteroidal anti-inflammatory drugs, phenytoin, sulfonylureas, etc.
  • CYP2C19 (strongly) which metabolises clonazepam, diazepam, phenytoin, etc.
  • CYP2B6 (weakly) which metabolises bupropion, cyclophosphamide, sertraline, tamoxifen, valproate, etc.

By so doing, fluvoxamine can increase serum concentration of the substrates of these enzymes.

The plasma levels of oxidatively metabolised benzodiazepines (e.g. triazolam, midazolam, alprazolam and diazepam) are likely to be increased when co-administered with fluvoxamine. However the clearance of benzodiazepines metabolised by glucuronidation (e.g. lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine. It appears that benzodiazepines metabolised by nitro-reduction (clonazepam, nitrazepam) are unlikely to be affected by fluvoxamine. Using fluvoxamine and alprazolam together can increase alprazolam plasma concentrations. If alprazolam is co-administered with fluvoxamine, the initial alprazolam dose should be reduced to the lowest effective dose.

Fluvoxamine and ramelteon co-administration is not indicated.

Fluvoxamine has been observed to increase serum concentrations of mirtazapine, which is mainly metabolised by CYP1A2, CYP2D6, and CYP3A4, by three- to four-fold in humans. Caution and adjustment of dosage as necessary are warranted when combining fluvoxamine and mirtazapine.

Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.

Fluvoxamine’s interaction with St John’s wort can lead to increased serotonin levels and potentially lead to serotonin syndrome.

Pharmacology

Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter. It has negligible affinity for the dopamine transporter or any other site, with the sole exception of the σ1 receptor. It behaves as a potent agonist at this receptor and has the highest affinity (36 nM) of any SSRI for doing so. This may contribute to its antidepressant and anxiolytic effects and may also afford it some efficacy in treating the cognitive symptoms of depression. Unlike some other SSRI, fluvoxamine’s metabolites are pharmacologically neutral.

Society and Culture

Manufacturers include BayPharma, Synthon, and Teva, among others. Luvox was notably used by Eric Harris, one of the Columbine shooters.

Book: The End of Mental Illness

Book Title:

The End of Mental Illness: How Neuroscience Is Transforming Psychiatry and Helping Prevent or Reverse Mood and Anxiety Disorders, ADHD, Addictions, PTSD, Psychosis, Personality Disorders, and More.

Author(s): Daniel G. Amen.

Year: 2020.

Edition: First (1st).

Publisher: Tyndale House Publishers.

Type(s): Hardcover, Paperback, Audiobook, and Kindle.

Synopsis:

Though incidence of these conditions is skyrocketing, for the past four decades standard treatment has not much changed, and success rates in treating them have barely improved, either. Meanwhile, the stigma of the “mental illness” label – damaging and devastating on its own – can often prevent sufferers from getting the help they need.

Brain specialist and bestselling author Dr. Daniel Amen is on the forefront of a new movement within medicine and related disciplines that aims to change all that. In The End of Mental Illness, Dr. Amen draws on the latest findings of neuroscience to challenge an outdated psychiatric paradigm and help readers take control and improve the health of their own brain, minimising or reversing conditions that may be preventing them from living a full and emotionally healthy life.

The End of Mental Illness will help you discover:

  • Why labelling someone as having a “mental illness” is not only inaccurate but harmful.
  • Why standard treatment may not have helped you or a loved one – and why diagnosing and treating you based on your symptoms alone so often misses the true cause of those symptoms and results in poor outcomes.
  • At least 100 simple things you can do yourself to heal your brain and prevent or reverse the problems that are making you feel sad, mad, or bad.
  • How to identify your “brain type” and what you can do to optimise your particular type.
  • Where to find the kind of health provider who understands and uses the new paradigm of brain health.

What is Person-Centred Therapy?

Introduction

Person-centred therapy, also known as person-centred psychotherapy, person-centred counselling, client-centred therapy and Rogerian psychotherapy, is a form of psychotherapy developed by psychologist Carl Rogers beginning in the 1940s and extending into the 1980s. Person-centred therapy seeks to facilitate a client’s self-actualising tendency, “an inbuilt proclivity toward growth and fulfilment”, via acceptance (unconditional positive regard), therapist congruence (genuineness), and empathic understanding.

It is one of the most influential and fundamental modalities of treatment in modern psychological practice, and is applied almost universally in modern psychotherapy. However, it is rarely used on its own; typically it is combined with other forms of therapy.

Background

Person-centred therapy, now considered a founding work in the humanistic school of psychotherapies, began with Carl Rogers, and is recognised as one of the major psychotherapy “schools” (theoretical orientations),[clarification needed] along with psychodynamic psychotherapy, psychoanalysis, classical Adlerian psychology, cognitive behavioural therapy, existential therapy, and others.

Rogers affirmed individual personal experience as the basis and standard for living and therapeutic effect. This emphasis contrasts with the dispassionate position which may be intended in other therapies, particularly the behavioural therapies. Living in the present rather than the past or future, with organismic trust, naturalistic faith in one’s own thoughts and the accuracy in one’s feelings, and a responsible acknowledgment of one’s freedom, with a view toward participating fully in our world, contributing to other peoples’ lives, are hallmarks of Rogers’ person-centred therapy. Rogers also claimed that the therapeutic process is essentially the accomplishments made by the client. The client having already progressed further along in their growth and maturation development, only progresses further with the aid of a psychologically favoured environment.

Although client-centred therapy has been criticised by behaviourists for lacking structure and by psychoanalysts for actually providing a conditional relationship, it has been shown to be an effective treatment.

What is Required for Therapeutic Change?

Rogers (1957; 1959) stated that there are six necessary and sufficient conditions required for therapeutic change:

  1. Therapist-client psychological contact: a relationship between client and therapist must exist, and it must be a relationship in which each person’s perception of the other is important.
  2. Client incongruence: that in-congruence exists between the client’s experience and awareness.
  3. Therapist congruence, or genuineness: the therapist is congruent within the therapeutic relationship. The therapist is deeply involved – they are not ‘acting’ – and they can draw on their own experiences (self-disclosure) to facilitate the relationship.
  4. Therapist unconditional positive regard: the therapist accepts the client unconditionally, without judgment, disapproval or approval. This facilitates increased self-regard in the client, as they can begin to become aware of experiences in which their view of self-worth was distorted or denied.
  5. Therapist empathic understanding: the therapist experiences an empathic understanding of the client’s internal frame of reference. Accurate empathy on the part of the therapist helps the client believe the therapist’s unconditional regard for them.
  6. Client perception: that the client perceives, to at least a minimal degree, the therapist’s unconditional positive regard and empathic understanding.

Core Conditions

It is believed that the most important factor in successful therapy is the relational climate created by the therapist’s attitude to their client. The therapist’s attitude is defined by the three conditions focused on the therapist, which are often called the core conditions (3, 4, and 5 of the above six conditions):

  1. Congruence: the willingness to transparently relate to clients without hiding behind a professional or personal façade.
  2. Unconditional positive regard: the therapist offers an acceptance and prizing for their client for who he or she is without conveying disapproving feelings, actions or characteristics and demonstrating a willingness to attentively listen without interruption, judgement or giving advice.
  3. Empathy: the therapist communicates their desire to understand and appreciate their client’s perspective.

Processes

Rogers believed that a therapist who embodies the three critical and reflexive attitudes (the three core conditions) will help liberate their client to more confidently express their true feelings without fear of judgement. To achieve this, the client-centred therapist carefully avoids directly challenging their client’s way of communicating themselves in the session in order to enable a deeper exploration of the issues most intimate to them and free from external referencing. Rogers was not prescriptive in telling his clients what to do, but believed that the answers to the clients’ questions were within the client and not the therapist. Accordingly, the therapists’ role was to create a facilitative, empathic environment wherein the client could discover the answers for him or herself.

Book: The Post-Traumatic Stress Disorder Sourcebook

Book Title:

The Post-Traumatic Stress Disorder Sourcebook, Revised and Expanded Second Edition: A Guide to Healing, Recovery, and Growth.

Author(s): Glenn R. Schiraldi (PhD).

Year: 2016.

Edition: Second (2nd).

Publisher: McGraw-Hill Education.

Type(s): Paperback and Kindle.

Synopsis:

The Post-Traumatic Stress Disorder Sourcebook, Revised and Expanded Second Edition introduces survivors, loved ones, and helpers to the remarkable range of treatment alternatives and self-management techniques available today to break through the pain and realise recovery and growth.

This updated edition incorporates all-new diagnostics from the DSM-5 and covers the latest treatment techniques and research findings surrounding the optimisation of brain health and function, sleep disturbance, new USDA dietary guidelines and the importance of antioxidants, early childhood trauma, treating PTSD and alcoholism, the relationship between PTSD and brain injury, suicide and PTSD, somatic complaints associated with PTSD, and more.